lesson 7.1 inborn errors of metabolism

5/20/2018 Lesson 7.1 Inborn Errors of Metabolism

1/119

Metabolic Diseases

Inborn Errors Of Metabolism (IEM)


2/119

A primer on metabolic disease in the neonate...


3/119

What is a metabolic disease?

Inborn errors of metabolism

inborn error : an inherited (i.e. genetic) disorder

metabolism : chemical or physical changes undergone by

substances in a biological system

any disease originating in our chemical individuality


4/119


Garrods hypothesis

product deficiency

substrate excess

toxic metabolite

A

D

B C


5/119


Small molecule disease

Carbohydrate

Protein

Lipid

Nucleic Acids

Organelle disease

Lysosomes

Mitochondria

Peroxisomes

Cytoplasm


6/119

How do metabolic diseases present in the neonate

?? Acute life threatening illness

encephalopathy - lethargy, irritability, coma

vomiting

respiratory distress

Seizures, Hypertonia

Hepatomegaly (enlarged liver) Hepatic dysfunction / jaundice

Odour, Dysmorphism, FTT (failure to thrive), Hiccoughs


7/119

How do you recognize a metabolic disorder ??

Index of suspicion

eg with any full-term infant who has no antecedent maternal fever or

PROM (premature rupture of the membranes) and who is sick enough towarrant a blood culture or LP, one should proceed with a few simple lab

tests.

Simple laboratory tests

Glucose, Electrolytes, Gas, Ketones, BUN (blood urea nitrogen),

Creatinine

Lactate, Ammonia, Bilirubin, LFT

Amino acids, Organic acids, Reducing subst.


8/119

Index of suspicion

Family History

Most IEMs are recessive - a negative family history is not

reassuring!

CONSANGUINITY, ethnicity, inbreeding

neonatal deaths, fetal losses

maternal family history

males - X-linked disorders

all - mitochondrial DNA is maternally inherited

A positive family history may be helpful!


9/119

Index of suspicion

History

CAN YOU EXPLAIN THE SYMPTOMS?

Timing of onset of symptoms

after feeds were started?

Response to therapies


10/119

Index of suspicion

Physical examination

Generaldysmorphisms (abnormality in shape or size), ODOUR

H&N - cataracts, retinitis pigmentosa

CNS - tone, seizures, tense fontanelle

Resp - Kussmauls, tachypnea

CVS - myocardial dysfunction

Abdo - HEPATOMEGALY

Skin - jaundice


11/119

Index of suspicion

Laboratory

ANION GAP METABOLIC ACIDOSIS

Normal anion gap metabolic acidosis

Respiratory alkalosis

Low BUN relative to creatinine

Hypoglycemia

especially with hepatomegaly

non-ketotic


12/119

A parting thought ...

Metabolic diseases are individually rare, but as a group are not

uncommon.

There presentations in the neonate are often non-specific at the

outset.

Many are treatable.

The most difficult step in diagnosis is considering the possibility!


13/119

INBORN ERRORS OF METABOLISM


14/119

Inborn Errors of Metabolism

An inherited enzyme deficiency leading to the disruption of normal

bodily metabolism

Accumulation of a toxic substrate (compound acted upon by an

enzyme in a chemical reaction)

Impaired formation of a product normally produced by the

deficient enzyme


15/119

Three Types

Type 1: Silent Disorders

Type 2: Acute Metabolic Crises

Type 3: Neurological Deterioration


16/119

Type 1: Silent Disorders

Do not manifest life-threatening crises

Untreated could lead to brain damage and developmental

disabilities

Example: PKU (Phenylketonuria)


17/119

PKU

Error of amino acids metabolism

No acute clinical symptoms

Untreated leads to mental retardation

Associated complications: behavior disorders, cataracts, skin

disorders, and movement disorders

First newborn screening test was developed in 1959

Treatment: phenylalaine restricted diet (specialized formulas

available)


18/119

Type 2: Acute Metabolic Crisis

Life threatening in infancy

Children are protected in utero by maternal circulation which

provide missing product or remove toxic substance

Example OTC (Urea Cycle Disorders)


19/119

OTC

Appear to be unaffected at birth

In a few days develop vomiting, respiratory distress, lethargy, and

may slip into coma.

Symptoms mimic other illnesses

Untreated results in death

Treated can result in severe developmental disabilities


20/119

Type 3: Progressive Neurological Deterioration

Examples: Tay Sachs disease

Gaucher disease

Metachromatic leukodystrophy

DNA analysis show: mutations


21/119

Mutations

Nonfunctioning enzyme results:

Early Childhood - progressive loss of motor and cognitive skills

Pre-Schoolnon responsive state

Adolescence - death


22/119

Other Mutations

Partial Dysfunctioning Enzymes

-Life Threatening Metabolic Crisis

-ADH

-LD

-MR

Mutations are detected by Newborn Screening and Diagnostic

Testing


23/119

Treatment

Dietary Restriction

Supplement deficient product

Stimulate alternate pathway

Supply vitamin co-factor

Organ transplantation

Enzyme replacement therapy

Gene Therapy


24/119

Children in School

Life long treatment

At risk for ADHD

LD

MR

Awareness of diet restrictions

Accommodations


25/119


Definition:

Inborn errors of metabolism occur from a group of rare genetic

disorders in which the body cannot metabolize food components

normally. These disorders are usually caused by defects in the enzymes

involved in the biochemical pathways that break down food components.

Alternative Names:

Galactosemia - nutritional considerations; Fructose intolerance -

nutritional considerations; Maple sugar urine disease (MSUD) - nutritional

considerations; Phenylketonuria (PKU) - nutritional considerations;

Branched chain ketoaciduria - nutritional considerations


26/119

Background:

Inborn errors of metabolism (IEMs) individually are rare but

collectively are common. Presentation can occur at any time, even in

adulthood.

Diagnosis does not require extensive knowledge of biochemical

pathways or individual metabolic diseases.

An understanding of the broad clinical manifestations of IEMs

provides the basis for knowing when to consider the diagnosis.

Most important in making the diagnosis is a high index of suspicion.

Successful emergency treatment depends on prompt institution of

therapy aimed at metabolic stabilization.


27/119

A geneticallydetermined

biochemicaldisorderin which aspecific enzymedefectproduces a

metabolic blockthat may have

pathologicconsequences at birth

(e.g., phenylketonuria) or in later life

(e.g., diabetes mellitus); called also

enzymopathyand genetotrophic

disease.
http://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/genetically.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/biochemical.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/disorder.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/enzyme.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/defect.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/metabolic_block.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/pathologic.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/phenylketonuria.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/diabetes_mellitus.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/enzymopathy.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/genetotrophic.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/genetotrophic.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/enzymopathy.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/diabetes_mellitus.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/phenylketonuria.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/pathologic.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/metabolic_block.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/defect.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/enzyme.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/disorder.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/biochemical.htmlhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/Terms/genetically.html


28/119

Metabolic disorders testable on Newborn Screen

Congenital Hypothyroidism

Phenylketonuria (PKU)

Galactosemia

Galactokinase deficiency

Maple syrup urine disease

Homocystinuria

Biotinidase deficiency
http://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/NIC48.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END184.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END84.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END86.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END86.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END84.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END184.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/NIC48.htm


29/119

Classification

Inborn Errors of Small molecule MetabolismExample: Galactosemia

Lysosomal storage diseases

Example: Gaucher's Disease

Disorders of Energy MetabolismExample Glycogen Storage Disease

Other more rare classes of metabolism error

Paroxysmal disorders

Transport disorders

Defects in purine and pyrimidine metabolism

Receptor Defects
http://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END84.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END81.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END80.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END80.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END80.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END80.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END81.htmhttp://localhost/var/www/apps/conversion/Local%20Settings/Temporary%20Internet%20Files/Content.IE5/OXU785EZ/END84.htm


30/119

Categories of IEMs are as follows:

Disorders of protein metabolism (eg, amino acidopathies, organic

acidopathies, and urea cycle defects)

Disorders of carbohydrate metabolism (eg, carbohydrate intolerance

disorders, glycogen storage disorders, disorders of gluconeogenesis

and glycogenolysis)

Lysosomal storage disorders

Fatty acid oxidation defects

Mitochondrial disorders

Peroxisomal disorders


31/119

Pathophysiology:

Single gene defects result in abnormalities in the synthesis or

catabolism of proteins, carbohydrates, or fats.

Most are due to a defect in an enzyme or transport protein, which

results in a block in a metabolic pathway.

Effects are due to toxic accumulations of substrates before the block,

intermediates from alternative metabolic pathways, and/or defects in energy

production and utilization caused by a deficiency of products beyond the

block.

Nearly every metabolic disease has several forms that vary in age of

onset, clinical severity and, often, mode of inheritance.


32/119

Frequency:

In the US: The incidence, collectively, is estimated to

be 1 in 5000 live births. The frequencies for each individual

IEM vary, but most are very rare. Of term infants who

develop symptoms of sepsis without known risk factors, as

many as 20% may have an IEM.

Internationally: The overall incidence is similar to

that of US. The frequency for individual diseases varies based

on racial and ethnic composition of the population.


33/119

Mortality/Morbidity:

IEMs can affect any organ system and usually do affect

multiple organ systems.

Manifestations vary from those of acute life-threatening

disease to subacute progressive degenerative disorder.Progression may be unrelenting with rapid life-threatening

deterioration over hours, episodic with intermittent

decompensations and asymptomatic intervals, or insidious with

slow degeneration over decades.


34/119


35/119

Purine metabolism


36/119

Adenine phosphoribosyltransferase deficiency


37/119

The normal function of adenine phosphoribosyltransferase

(APRT) is the removal of adenine derived as metabolic waste from the

polyamine pathway and the alternative route of adenine metabolism to

the extremely insoluble 2,8-dihydroxyadenine, which is operative when

APRT is inactive. The alternative pathway is catalysed by xanthine

oxidase.


38/119

Hypoxanthine-guanine phosphoribosyltransferase (HPRT,

EC 2.4.2. 8)

HGPRTcatalyses the transfer of the phosphoribosyl

moiety of PP-ribose-P to the 9 position of the purine ring of

the bases hypoxanthine and guanine to form inosinemonophospate (IMP) and guanosine monophosphate

(GMP) respectively.

HGPRT is a cytoplasmic enzyme present in virtually

all tissues, with highest activity in brain and testes.


39/119

The salvage pathway of the

purine bases, hypoxanthine

and guanine, to IMP and

GMP, respectively,

catalysed by HGPRT (1) in

the presence of PP-ribose-

P. The defect in HPRT is

shown.


40/119

The importance of HPRT in the normal interplay between

synthesis and salvage is demonstrated by the biochemical and clinical

consequences associated with HPRT deficiency.

Gross uric acid overproduction results from the inability to

recycle either hypoxanthine or guanine, which interrupts the inosinate

cycle producing a lack of feedback control of synthesis, accompanied by

rapid catabolism of these bases to uric acid. PP-ribose-P not utilized in

the salvage reaction of the inosinate cycle is considered to provide an

additional stimulus to de novo synthesis and uric acid overproduction.


41/119

The defect is readily detectable in erythrocyte

hemolysates and in culture fibroblasts. HGPRT is determined by a gene on the long arm of the

x-chromosome at Xq26.

The disease is transmitted as an X-linked recessive trait.

Lesch-Nyhan syndrome

Allopurinal has been effective reducing concentrations

of uric acid.


42/119

Phosphoribosyl pyrophosphate synthetase (PRPS, EC 2.7.6.1)

catalyses the transfer of the pyrophosphate group of ATP to ribose-5-

phosphate to form PP-ribose-P.

The enzyme exists as a complex aggregate of up to 32 subunits,

only the 16 and 32 subunits having significant activity. It requires Mg2+,

is activated by inorganic phosphate, and is subject to complex regulation

by different nucleotide end-products of the pathways for which PP-ribose-

P is a substrate, particularly ADP and GDP.

Phosphoribosyl pyrophosphate synthetase superactivity


43/119

PP-ribose-P acts as an allosteric regulator of the first specific

reaction of de novo purine biosynthesis, in which the interaction of

glutamine and PP-ribose-P is catalysed by amidophosphoribosyl

transferase, producing a slow activation of the amidotransferase by

changing it from a large, inactive dimer to an active monomer.

Purine nucleotides cause a rapid reversal of this process,

producing the inactive form.

Variant forms of PRPS have been described, insensitive to

normal regulatory functions, or with a raised specific activity. This

results in continuous PP-ribose-P synthesis which stimulates de novo

purine production, resulting in accelerated uric acid formation and

overexcretion.


44/119

The role of PP-ribose-P in the de novo synthesis of IMP and adenosine

(AXP) and guanosine (GXP) nucleotides, and the feedback control normally

exerted by these nucleotides on de novo purine synthesis.


45/119

Purine nucleoside phosphorylase(PNP, EC 2.4.2.1)

PNP catalyses the degradation of the nucleosides inosine,

guanosine or their deoxyanalogues to the corresponding base.

The mechanism appears to be the accumulation of purine

nucleotides which are toxic to T and B cells.

Although this is essentially a reversible reaction, base

formation is favoured because intracellular phosphate levels normally

exceed those of either ribose-, or deoxyribose-1-phosphate.

The enzyme is a vital link in the 'inosinate cycle' of the purine

salvage pathway and has a wide tissue distribution.

Purine nucleotide phosphorylase deficiency


46/119

The necessity of purine nucleoside phosphorylase (PNP) for the normal catabolism andsalvage of both nucleosides and deoxynucleosides, resulting in the accumulation of

dGTP, exclusively, in the absence of the enzyme, since kinases do not exist for the other

nucleosides in man. The lack of functional HGPRT activity, through absence of substrate,

in PNP deficiency is also apparent.


47/119

The importance of adenosine deaminase (ADA) for the catabolism of dA, but not A, and

the resultant accumulation of dATP when ADA is defective. A is normally salvaged by

adenosine kinase (see Km

values of A for ADA and the kinase, AK) and deficiency of

ADA is not significant in this situation

Adenine deaminase deficiency


48/119

The role of AMPDA in the deamination of AMP to IMP, and the recorversion of the

latter to AMP via AMPS, thus completing the purine nucleotide cycle which is of

particular importance in muscle.

Myoadenylate deaminase (AMPDA) deficiency


49/119

Purine and pyrimidine degradation


50/119

PRPP synthesis

1=ribokinase 2=ribophosphatepyrophosphokinase 3=phosphoribosyl transferase


51/119


52/119

Salvage pathway of purine

PRPP Purine ribonucleotide

purine PPi

Adenine + PRPP Adenylate + PPi

(AMP)

Mg 2+

APRTase

Catalyzed by adenine phosphoribosyl transferase (APRTase)


53/119

IMP and GMP interconversion

Hypoxanthine + PRPP Inosinate + PPi

( IMP)

Mg 2+

HGPRTase

Guanine + PRPP Guanylate + PPi

(GMP)

Mg 2+

HGPRTase

HGPRTase = Hypoxanthine-guanine phosphoribosyl transferase


54/119

i d


55/119

purine reused

1=adenine phosphoribosyl

transferase

2=HGPRTase


56/119


57/119

Formation of uric acid from hypoxanthine and xanthine catalysed

by xanthine dehydrogenase (XDH).


58/119


59/119

Intracellular uric acid crystal under polarised light (left) and under non-polarised light

(right)

With time, elevated levels of uric acid in the blood may lead to deposits around

joints. Eventually, the uric acid may form needle-like crystals in joints, leading to

acute gout attacks. Uric acid may also collect under the skin as tophi or in the

urinary tract as kidney stones.


60/119

Additional Gout Foot Sites: Inflamation In Joints Of Big Toe, Small Toe And Ankle

Gout-Early Stage: No Joint Damage

Gout-Late Stage: Arthritic Joint


61/119

Disorders of pyrimidine metabolism


62/119


63/119

The UMP synthase (UMPS) complex, a bifunctional protein comprising the enzymes

orotic acid phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate

decarboxylase (ODC), which catalyse the last two steps of the de novo pyrimidine

synthesis, resulting in the formation of UMP. Overexcretion formation can occur by the

alternative pathway indicated during therapy with ODC inhibitors.

Hereditary orotic aciduria


64/119

Dihydropyrimidine dehydrogenase (DHPD) is responsible for the catabolism of the end-products of

pyrimidine metabolism (uracil and thymine) to dihydrouracil and dihydrothymine. A deficiency of

DHPD leads to accumulation of uracil and thymine. Dihydropyrimidine amidohydrolase (DHPA)

catalyses the next step in the further catabolism of dihydrouracil and dihydrothymine to amino acids. A

deficiency of DHPA results in the accumulation of small amounts of uracil and thymine together with

larger amounts of the dihydroderivatives.


65/119

The role of uridine monophosphate hydrolases (UMPH) 1 and 2 in

the catabolism of UMP, CMP, and dCMP (UMPH 1), and dUMP

and dTMP (UMPH 2).


66/119

CDP-choline phosphotransferase catalyses the last step in the synthesis

of phosphatidyl choline. A deficiency of this enzyme is proposed as the

metabolic basis for the selective accumulation of CDO-choline in the

erythrocytes of rare patients with an unusual form of haemolytic

anaemia.

CDP-choline phosphotransferase deficiency


67/119


68/119

WHAT IS TYROSINEMIA?

Hereditary tyrosinemia is a genetic inborn error of metabolism

associated with severe liver disease in infancy. The disease is inherited in an

autosomal recessive fashion which means that in order to have the disease,

a child must inherit two defective genes, one from each parent. In families

where both parents are carriers of the gene for the disease, there is a one in

f o u r r i s k t h a t a c h i l d w i l l h a v e t y r o s i n e m i a.

About one person in 100 000 is affected with tyrosinemia globally.


69/119

HOW IS TYROSINEMIA CAUSED?

Tyrosine is an amino acid which is found in most animal

and plant proteins. The metabolism of tyrosine in humans takes

p l a c e p r i m a r i l y i n t h e l i v e r.

Tyrosinemia is caused by an absence of the enzyme

fumarylacetoacetate hydrolase (FAH) which is essential in the

metabolism of tyrosine. The absence of FAH leads to an

accumulation of toxic metabolic products in various body tissues,

which in turn results in progressive damage to the liver and

k i d n e y s.

WHAT ARE THE SYMPTOMS OF TYROSINEMIA?


70/119

WHAT ARE THE SYMPTOMS OF TYROSINEMIA?

The clinical features of the disease ten to fall into two categories, acute and chronic.

In the so-called acute form of the disease, abnormalities appear in the first month of life.Babies may show poor weight gain, an enlarged liver and spleen, a distended abdomen,

swelling of the legs, and an increased tendency to bleeding, particularly nose bleeds.

Jaundice may or may not be prominent. Despite vigorous therapy, death from hepatic

failure frequently occurs between three and nine months of age unless a liver

transplantation is performed.

Some children have a more chronic form of tyrosinemia with a gradual onset and less

severe clinical features. In these children, enlargement of the liver and spleen are

prominent, the abdomen is distended with fluid, weight gain may be poor, and vomiting

and diarrhoea occur frequently. Affected patients usually develop cirrhosis and its

complications. These children also require liver transplantation.

Methionine synthesis


71/119

Methionine synthesis


72/119

Homocystinuria

Homocystinuria


73/119

Homocystinuria


74/119


75/119

Figure 1: the structures of tyrosine, phenylalanine and homogentisic acid


76/119

Phenylketonuria


77/119


78/119


79/119


80/119

Maple syrup urine disease


81/119

p y p


82/119


83/119

Albinism


84/119


85/119

This excess can be caused by an increase in production by the body, by under-elimination

of uric acid by the kidneys or by increased intake of foods containing purines which are

metabolized to uric acid in the body. Certain meats, seafood, dried peas and beans are

particularly high in purines. Alcoholic beverages may also significantly increase uric acid

levels and precipitate gout attacks.


86/119

Pyruvate kinase (PK) deficiency:


87/119

This is the next most common red cell enzymopathy after G6PD

deficiency, but is rare. It is inherited in a autosomal recessive pattern

and is the commonest cause of the so-called "congenital non-

spherocytic haemolytic anaemias" (CNSHA).

PK catalyses the conversion of phosphoenolpyruvate to pyruvate with

the generation of ATP. Inadequate ATP generation leads to premature

red cell death.

There is considerable variation in the severity of haemolysis. Most

patients are anaemic or jaundiced in childhood. Gallstones,

splenomegaly and skeletal deformities due to marrow expansion may

occur. Aplastic crises due to parvovirus have been described.


88/119

Hereditary hemolytic anemia


89/119


90/119

Blood film: PK deficiency:

Characteristic "prickle cells" may be seen.


91/119

Drug induced hemolytic anemia

Glycogen storage disease


92/119

y g g


93/119

Case Description

A female baby was delivered normally after an

uncomplicated pregnancy. At the time of the infants

second immunization, she became fussy and was

seen by a pediatrician, where examination revealed

an enlarged liver. The baby was referred to a

gastroenterologist and later diagnosed to have

Glycogen Storage Disease Type IIIB

GlycogenosesDisorder Affected Tissue Enzyme Inheritance Gene Chromosome
http://mednet.hsc.usf.edu/ovidweb/ovidweb.cgi?View+Image=00005005-200202000-00023|FF1&S=AIPPPPOPLFOJMK00D


94/119

y

Type 0 Liver Glycogen synthase AR GYS2[125] 12p12.2[121]

Type IA Liver, kidney, intestine Glucose-6-phosphatase AR G6PC[96] 17q21[13][94]

Type IB Liver Glucose-6-phosphate transporter (T1) AR G6PTI[57][104] 11q23[2][81][104][155]

Type IC Liver Phosphate transporter AR 11q23.3-24.2[49][135]

Type IIIA Liver, muschle, heart Glycogen debranching enzyme AR AGL 1p21[173]

Type IIIB Liver Glycogen debranching enzyme AR AGL 1p21[173]

Type IV Liver Glycogen phosphorylase AR PYGL[26] 14q21-22[118]

Type IX Liver, erythrocytes, leukocytes Liver isoform of -subunit of liver and muscle

phosphorylase kinase

X-Linked PHKA2 Xp22.1-p22.2[40][68][162][165]

Liver, muscle, erythrocytes,

leukocytes

-subunit of liver and muscle PK AR PHKB 16q12-q13[54]

Liver Testis/liver isoform of -subunit of PK AR PHKG2 16p11.2-p12.1[28][101]


95/119

Glycogen


96/119


97/119


98/119


99/119


100/119

Type 0Glycogen Storage Diseases


101/119

Type I

Type II

Type IV

Type VII

Glycogen Storage Disease


102/119

y g g

Type IIIb

Deficiency of debranching enzyme in the liver needed to

completely break down glycogen to glucose

Hepatomegaly and hepatic symptoms

Usually subside with age

Hypoglycemia, hyperlipidemia, and elevated liver transaminases

occur in children

GSD Type III


103/119

Type III

Debranching Enzyme


104/119

Debranching Enzyme

Amylo-1,6-glucosidase

Isoenzymes in liver, muscle and heart

Transferase function

Hydrolytic function

Genetic Hypothesis


105/119

Genetic Hypothesis

The two forms of GSD Type III are caused by different mutations

in the same structural Glycogen Debranching Enzyme gene

Amylo-1 6-Glucosidase Gene


106/119

Amylo 1,6 Glucosidase Gene

The gene consists of 35 exons spanning at least 85 kbp of DNA

The transcribed mRNA consists of a 4596 bp coding region and a

2371 bp non-coding region

Type IIIa and IIIb are identical except for sequences in non-

translated area

The tissue isoforms differ at the 5 end

M d G


107/119

Mutated Gene

Approximately 16 different mutations identified

Most mutations are nonsense

One type caused by a missense mutation

Where Mutation Occurs


108/119

Where Mutation Occurs

The GDE gene is located on chromosome

1p21, and contains 35 exons translated into

a monomeric protein

Exon 3 mutations are specific to the type

IIIb, thus allowing for differentiation

I h i


109/119

Inheritance


Autosomal recessive disorder

Incidence estimated to be between 1:50,000 and 1:100,000births per year in all ethnic groups

Herling and colleagues studied incidence and frequency in

British Columbia

2.3 children per 100,000 births per year


110/119

Inheritance

Single variant in North African Jews in Israel shows both liver and muscle

involvement (GSD IIIa)

Incidence of 1:5400 births per year

Carrier frequency is 1:35

I h it


111/119

Inheritance

G g

G

g

GG Gg

Gg gg

GG = normal

Gg = carrier

Gg = GSD

Both parents are carriers in the case.


112/119

Inheritance

normal

carrier

GSD

Baby

Clinical Features


113/119

Clinical Features

Hepatomegaly and fibrosis in childhood

Fasting hypoglycemia (40-50 mg/dl)

Hyperlipidemia

Growth retardation

Elevated serum transaminase levels(aspartate aminotransferase and alanine aminotransferase > 500 units/ml)

Common presentation

Clinical Features


114/119

Splenomegaly

Liver cirrhosis

Clinical Features

Less Common


115/119

Galactosemia is an inherited disorder that affects the way the body breaks down

certain sugars. Specifically, it affects the way the sugar called galactose is broken

down. Galactose can be found in food by itself. A larger sugar called lactose,

sometimes called milk sugar, is broken down by the body into galactose and glucose.

The body uses glucose for energy. Because of the lack of the enzyme (galactose-1-

phosphate uridyl transferase) which helps the body break down the galactose, it then

builds up and becomes toxic. In reaction to this build up of galactose the body makes

some abnormal chemicals. The build up of galactose and the other chemicals can cause

serious health problems like a swollen and inflamed liver, kidney failure, stunted

physical and mental growth, and cataracts in the eyes. If the condition is not treated

there is a 70% chance that the child could die.


116/119


117/119

Lysomal storage diseases


118/119

The pathways are shown for the formation

and degradation of a variety ofsphingolipids, with the hereditary metabolic

diseases indicated.

Note that almost all defects in sphingolipidmetabolism result in mental retardation and

the majority lead to death. Most of the

diseases result from an inability to breakdown sphingolipids (e.g., Tay-Sachs,

Fabry's disease).


119/119

lesson 7.1 inborn errors of metabolism

Documents

hiccoughs5202018 lesson

therapies5202018 lesson

genetic disorder metabolism

metabolic disorder

metabolic diseases present

index of suspicionhistory

negative family history

positive family history